Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts

Abstract

Aims: We investigated whether polymorphisms in candidate genes involved in lipid metabolism and type 2 diabetes are related to liver fat content. Methods: Liver fat content was measured using proton magnetic resonance spectroscopy ( 1 H-MRS) in 302 Finns, in whom single nucleotide polymorphisms (SNPs) in acyl-CoA synthetase long-chain family member 4 (ACSL4), adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2), and the three peroxisome proliferator-activated receptors (PPARA, PPARD, and PPARG) were analyzed. To validate our findings, SNPs significantly associated with liver fat content were studied in two independent cohorts and related to surrogate markers of liver fat content. Results: In the Finnish subjects, polymorphisms in ACSL4 (rs7887981), ADIPOR2 (rs767870), and PPARG (rs3856806) were significantly associated with liver fat content measured with 1 H-MRS after adjusting for age, gender, and BMI. Anthropometric and circulating parameters were comparable between genotypes. In the first validation cohort of w 600 Swedish men, ACSL4 rs7887981 was related to fasting insulin and triglyceride concentrations, and ADIPOR2 rs767870 to serum g glutamyltransferase concentrations after adjusting for BMI. The SNP in PPARG (rs3856806) was not significantly associated with any relevant metabolic parameter in this cohort. In the second validation cohort of w3000 subjects from Western Finland, ADIPOR2 rs767870, but not ACSL4 rs7887981 was related to fasting triglyceride concentrations. Conclusions: Genetic variation, particularly in the ADIPOR2 gene, contributes to variation in hepatic fat accumulation in humans.

Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent

“…2 Carriers of the PNPLA3 I148M allele have more hepatic fat 4,13 in the liver, and in our obese cohort they have increased circulating levels of ALT and AST. We went on to examine whether carriers of the 148M allele were more insulin resistant or had any impairment in glucose tolerance.…”

Long-chain acyl-CoA synthetase 4 modulates prostaglandin E2 release from human arterial smooth muscle cells

“…Furthermore, based on correlative studies, ACSL4 has been proposed to promote hepatic TAG synthesis ( 35,36 ), to contribute to human hepatocellular carcinoma and adenocarcinoma ( 37,38 ), and to have important effects in cognitive function and neuromuscular disease ( 15,(39)(40)(41). ACSL4 gene expression was also found to be signifi cantly upregulated in livers of insulin-resistant human subjects with nonalcoholic fatty liver disease ( 42 ), and recently, a polymorphism in ACSL4 was found to be signifi cantly associated with liver fat content ( 36 ). The biological function of ACSL4 in SMCs and other vascular cells has been unknown.…”

Hepatic adiponectin receptors (ADIPOR) 1 and 2 mRNA and their relation to insulin resistance in obese humans

“…Specifically, adiponectin signalling alleviated or prevented NASH in mice, 33,34 and associations of hypoadiponectinaemia with fatty liver and/or NASH have been reported in humans. 35,36 Furthermore, genetic studies revealed associations of ADIPOR1/2 with IR and liver fat content, 37,38 and overexpression of ADIPOR1/2 has been shown to potentiate subeffective doses of adiponectin. 39 We therefore suggest that the increased ADIPOR1/2 mRNA expression in obese, insulin-resistant subjects represents a mechanism that may partially compensate for reduced plasma adiponectin.…”